Project Summary Mild cognitive impairment (MCI) can be a transitional stage between normal aging and Alzheimer's Disease (AD). Obstructive sleep apnea (OSA), a condition in which there is recurrent upper airway obstruction during sleep leading to nocturnal hypoxia and cognitive dysfunction, is present in 58.7% of MCI patients, yet it is rarely diagnosed or treated. OSA can be effectively managed with continuous positive airway pressure (CPAP), a pressurized nasal mask worn during sleep, but there is little information on its efficacy in this population, thus limiting adoption. The primary goal of this proposal is therefore to evaluate whether treatment of OSA in amnestic MCI (aMCI) with CPAP delays cognitive decline and preserves everyday function. The study investigators have successfully completed an NIA Alzheimer's Disease Pilot R01 Clinical Trial (?Memories?) using a quasi-experimental design that provided valuable preliminary and feasibility data (one- year follow-up, two sites, n=68). It consisted of three aMCI groups: 1) CPAP adherent intervention group; and two control groups 2a) CPAP non-adherent and 2b) No OSA. They demonstrated that 1) progression of cognitive impairment was reduced with CPAP; and 2) baseline MRI differences were noted in hippocampal and medial temporal lobe subregions, several of which improved in CPAP adherent patients. While clinically compelling, these findings were not statistically significant (p=0.125 and higher) due to the study sample size. The specific aims of the current proposal are to confirm and expand these findings in a larger four-site study (n=460) using the approach the study team has successfully implemented previously. Aim 1 will evaluate the hypothesis that declines in one-year memory/processing speed (Digit Symbol-Coding test) are attenuated in CPAP adherent (n=200) vs CPAP non-adherent (n=160) aMCI. Aim 2 will evaluate brain MRIs to test the following hypotheses: 1) Right hippocampal hypertrophy noted at baseline in the preliminary study is a hallmark of OSA--the study will compare brain MRIs in OSA+ (n=360) to OSA- (n=100) participants; and 2) At one-year follow-up, CPAP adherent participants will have reductions in atrophy, with partial normalization of the right hippocampal area hypertrophy noted at baseline when compared to CPAP non-adherent participants. Aim 3 will be an exploratory cerebrospinal fluid (CSF) sub-study to evaluate AB42, total tau, phosphorylated tau, as well as pathway biomarkers F2-isoprostane (oxidative stress), hypoxia-inducible factor-1a (OSA-related intermittent hypoxia), and vascular endothelial growth factor (neuroprotective). CPAP adherence can be measured precisely with a sensor that determines hours of use and propensity score analysis will be used to effectively control for confounding variables related to group allocation and outcome. The findings from this large-scale study, adequately powered for clinical and statistical significance based on successful prior trial results, have the potential to change the care of millions of MCI patients as they seek to mitigate the devastating consequences of progressive cognitive decline.